Desmoplakin and periplakin genetically and functionally contribute to eosinophilic esophagitis.

Abstract

Eosinophilic esophagitis (EoE) is a chronic allergic inflammatory disease with a complex underlying genetic etiology. Herein, we conduct whole-exome sequencing of a multigeneration EoE pedigree (discovery set) and 61 additional multiplex families with EoE (replication set). A series of rare, heterozygous, missense variants are identified in the genes encoding the desmosome-associated proteins DSP and PPL in 21% of the multiplex families. Esophageal biopsies from patients with these variants retain dilated intercellular spaces and decrease DSP and PPL expression even during disease remission. These variants affect barrier integrity, cell motility and RhoGTPase activity in esophageal epithelial cells and have increased susceptibility to calpain-14-mediated degradation. An acquired loss of esophageal DSP and PPL is present in non-familial EoE. Taken together, herein, we uncover a pathogenic role for desmosomal dysfunction in EoE, providing a deeper mechanistic understanding of tissue-specific allergic responses.

• Authors: Tetsuo Shoda, Kenneth M Kaufman, Ting Wen, Julie M Caldwell, Garrett A Osswald, Pathre Purnima, Nives Zimmermann, Margaret H Collins, Kira Rehn, Heather Foote, Michael D Eby, Wenying Zhang, Netali Ben-Baruch Morgenstern, Adina Y Ballaban, Jeff E Habel, Leah C Kottyan, J Pablo Abonia, Vincent A Mukkada, Philip E Putnam, Lisa J Martin, Marc E Rothenberg
• Journal: Nature communications (Nat Commun) Vol. 12 Issue 1 Pg. 6795 (11 23 2021) ISSN: 2041-1723 [Electronic] England
• PMID: 34815391 (Publication Type: Journal Article, Observational Study, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. The Author(s).

Chemical References

• DSP protein, human
• Desmoplakins
• PPL protein, human
• Plakins
• CAPN14 protein, human
• Calpain

Topics

• Adolescent
• Biopsy
• Calpain (metabolism)
• Case-Control Studies
• Child
• DNA Mutational Analysis
• Desmoplakins (genetics, metabolism)
• Desmosomes (pathology)
• Eosinophilic Esophagitis (genetics, pathology)
• Esophageal Mucosa (cytology, pathology)
• Female
• HEK293 Cells
• HaCaT Cells
• Heterozygote
• Humans
• Male
• Mutation, Missense
• Plakins (genetics, metabolism)
• Proteolysis
• RNA-Seq
• Single-Cell Analysis
• Exome Sequencing